Transmucosal pharmacuetical administration form

ABSTRACT

Planiform transmucosal pharmaceutical administration forms are disclosed, comprising a solid solution of the active ingredient in a phosphatidyl fraction, or a mixture of said phosphatidyl fraction with a copolymer of maleic acid and an alkyl vinyl ether. The administration forms are characterised by a low solubility in the buccal cavity, which gives a rapid and constant active ingredient release over an extended period. The above are particularly suitable for the treatment of the abuse of and dependence on addictive drugs.

The invention relates to administration forms which are preferablyplaniform and which form liquid-crystalline structures or phases in anaqueous environment, in particular to oral administration forms whichcan be used to permit controlled absorption of active compounds in theoral cavity, in particular in the unkeratinized regions, and whichpossess a matrix which is based on phospholipids as basic substances. Inparticular, the invention relates to administration forms of said typewhich are configured in the form of wafers. The invention alsoencompasses a process for producing these administration forms.

The invention enables a wide spectrum of active compounds, e.g. activecompounds which act in the CNS (central nervous system), in thecardiovascular system, in the muscle and skeletal system and in therespiratory system of the human body, and also active compounds whichact as antiinfective agents, as antibiotics and as hormones, to bedelivered in a controlled manner to the oral mucosa.

Preferred active compounds which come into consideration for theadministration form according to the invention are those which aresuitable for treating drug abuse or drug dependence, in particular fortreating nicotine dependence and alcohol dependence of differinggenesis. The following substances or substance classes are particularlysuitable for this indication: 7-azabicyclo(2.2.1)heptane and -hepteneand their derivatives; ebibatidine and derivatives; fused indolederivatives; benzylidene and cinnamylidene-annabasiene; mecamylamine,hypericin, the cannabinoid receptor (CB1) antagonist SR 141716,befloxatone, oxazolidinone derivatives such as pemoline, buproprion andthe active compound CP-52655, and also the acid addition salts of theabovementioned substances.

The active compounds, their preparation and their pharmacologicaleffects are described in the following U.S. patent specifications: U.S.Pat. No. 6,255,490; U.S. Pat. No. 6,177,451; U.S. Pat. No. 6,117,889;U.S. Pat. No. 5,998,409 and U.S. Pat. No. 5,977,144.

Pharmaceutical administration forms, e.g. buccal and sublingual tablets,which release active compounds in the oral cavity, with the activecompounds then being absorbed through the oral mucosa, are advantageousin a variety of ways. They facilitate the oral administration ofmedicaments to certain patients who experience difficulty in ingestingother oral medicinal forms, e.g. because of problems with swallowing.Since the absorption takes place through the oral mucosa, and with thegastrointestinal tract being circumvented, rapid onset of effect andhigh active compound utilization are ensured. In addition to sublingualor buccal tablets, planiform, wafer-like administration forms (alsotermed wafers) are also suitable for use as oral medicinal forms whichexhibit the abovementioned properties. Because of their low layerthickness and their ability to disintegrate, or be dissolved, rapidly,these wafers are particularly suitable for rapidly releasing medicamentsand other active compounds in the oral cavity. As a rule, suchwafer-like medicinal forms are constructed from film-forming,water-soluble polymers, e.g. particular cellulose derivatives. Oncontact with water or saliva, the wafer matrix structure, which isformed by the polymers, decomposes, or the structure is dissolved, andthe active compounds which are present in it are released. The onset,and the chronological course, of the active compound release depend to alarge extent on the thickness of the medicinal form (of the wafer) andon the nature of the matrix structure. The structure of the matrixdetermines the release (profile); the nature of the polymer, or thenature and composition of the polymer mixture, determines the adherenceto the mucosa. Consequently, the thickness of such administration formsis essentially determined by the nature and quantity of the activecompound which they contain and are to release. As the thicknessincreases, the decomposition or dissolution of the wafer iscorrespondingly retarded. In particular, the relatively thick wafers,but also those having a relatively low thickness, tend, because of theirflat, smooth form and the delayed disintegration, to adhere, and stick,to the pallet or to other mucosal surfaces in the oral cavity. This isdetermined, on the one hand, by the polymer layers which dissolvesuperficially.

DE-A-100 32 456 and DE-A-101 07 659 describe wafers which have beendeliberately configured to exhibit a reduced tendency to adhere or stickto the oral mucosa and to have, as their aim, an accelerated release ofthe active compound. The dwell time of these administration forms at thesite of administration (e.g. the oral cavity), or the disintegrationtime, is preferably in the range from 5 sec to 1 min, more preferably inthe range from 10 sec to 1 min and most preferably in the range from 10sec to 30 sec. The matrix of these administration forms contains, asbasic substances, a water-soluble polymer or mixtures of such polymers.In this connection, preference is given to using synthetic or partiallysynthetic polymers, or biopolymers of natural origin, which arefilm-forming and water-soluble and/or which are also suitable, forexample, for forming foams.

These documents describe polymers which are preferably selected from thegroup which comprises cellulose derivatives, polyvinyl alcohol,polyacrylates and polyvinylpyrrolidone as being particularly suitablecarrier substances (matrix). The cellulose derivatives which areparticularly preferred are hydroxypropylmethyl cellulose, carboxymethylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose and methylcellulose, as well as other substituted cellulose derivatives.Preference is likewise given, in these documents, to water-solublepolysaccharides which are of vegetable, microbial or synthetic origin,in particular polysaccharides which are not cellulose derivatives, forexample pullulan, xanthan, alginates, dextrans, agar-agar, pectins andcarrageen. Furthermore, proteins, preferably gelatin or othergel-forming proteins, and also protein hydrolysates, are also mentioned.The carrier materials which are suitable in the abovementioned patentsor laid-open specifications likewise include caseinates, whey andvegetable proteins, gelatin and (chicken) egg white, and mixturesthereof.

EP-B-0 450 141 discloses a carrier material for administering activecompounds, which material is of such a composition that it dissolvesrapidly on contact with saliva after having been taken orally. Thismaterial is a porous, dehydrated skeleton-like carrier substance whichis in particular based on proteins, polysaccharides and/orphorspholipids, such as lecithin, without, however, said lecithin beingspecified. The gelatin-polysaccharide carriers which are described canalso be used in the form of wafers. The carrier substances are at thelatest rehydrated on contact with saliva and are thereby given a tackysurface which results in the administration form adhering in the oralcavity.

The wafer systems which are described in said prior art, and theirphysicochemical construction, suffer from the disadvantage that

-   -   1. they dissolve rapidly, which means that any longer-term        contact of the active compound with the mucosa, for the purpose        of enabling the active compound to be absorbed in the oral        region, either does not occur or only occurs to a very limited        extent,    -   2. even if it maintains contact with the mucosa for a relatively        long period, the matrix only acts as scaffolding which does not        promote penetration.

These properties are disadvantageous for the mucosal administration ofactive compounds which have to be absorbed rapidly, i.e. which require arapid onset of effect and which at the same time have to ensure aconstant blood level over a relatively long period. These activecompounds are, in particular, the above-mentioned substances which aresuitable for treating the abuse of addiction-inducing drugs and theirdependence on these drugs.

The object of the present invention is therefore to provide a planiformor wafer-like administration system which

-   -   1. adheres, for a relatively long period, to the oral mucosa, in        particular in the area of the frenulum, of the ventral tongue        region or in the floor of the mouth, i.e. the unkeratinized        region of the oral cavity,    -   2. holds the active compound available in a form which permits        absorption, in the oral region, which is both rapid and constant        over a relatively long period,    -   3. is tasteless or conveys the sensation of tastelessness.

According to the invention, this object is achieved by the parentsubstance of the transmucosal administration form being composed of asolid solution of the active compound

-   -   a) in a phosphatidylcholine whose fatty acid residues are at        least 90% saturated, or    -   b) in a mixture of the phosphatidylcholine mentioned under a)        and a copolymer composed of maleic acid and an alkyl vinyl        ether.

The parent substance in accordance with a) and b) can additionallycontain further pharmaceutically tolerated adjuvants and additives, forexample a polyvinyl-pyrrolidone of medium chain length, with thepolyvinylpyrrolidone also serving to improve the taste of theadministration form according to the invention.

The phosphatidylcholine fractions Epikuron 180 and/or Epikuron 180Hhave, in particular, proved suitable for the administration formaccording to the invention.

When they are dissolved in pure alcohol, it is possible to use thesephosphatidylcholines to prepare, by drying, solid transparent films inwhich the active compound is present as a solid solution. These filmsadhere to the oral mucosa for a sufficiently long period. When watergains access to these films, myelin-like structures, in which the activecompound is still dissolved, issue from the film surface. Thesestructures are not vesicular active compound-“encapsulated” microscopicunits but, rather, lamellar mesophases in whose lamellar regions theactive compound is present in molecular form. These lamellar mesophasesare particularly suitable for becoming attached to the mucosa.

This myelin formation can be controlled, right through to aspontaneously emulsifying gel system similar to a bore oil emulsion,depending on the content of residual solvent (ethanol) or additions ofsmall quantities of pure hydrocarbons (e.g. low-viscosity paraffin) ortriglycerides of low hydroxyl number.

1. A planiplaniform transmucosal pharmaceutical administration formwhich is distinguished by low solubility within the oral cavity andrelease of active compound which is rapid and constant over a relativelylong period, characterized in that it is composed of a solid solution ofthe active compound a) in a phosphatidylcholine fraction in which thefatty acid residues are at least 90% saturated, or b) in a mixture ofthe phosphatidylcholine fraction specified under a) and a copolymercomposed of maleic acid and an alkyl vinyl ether, and, whereappropriate, further pharmaceutically tolerated adjuvants and additives.2. The administration form as claimed in claim 1, characterized in thatit comprises at least 80% by weight of the phosphatidylcholine fractionin accordance with a).
 3. The administration form as claimed in claim 1,characterized in that it comprises polyvinylpyrrolidone as additive. 4.The administration form as claimed in claim 1, characterized in that theactive compound is suitable for treating the abuse of addiction-inducingdrugs and dependence on these drugs.
 5. The administration form asclaimed in claim 1, characterized in that the active compound is a fusedindole derivative and/or its acid addition salt.
 6. The administrationform as claimed in claim 1, characterized in that the active compound is7-azabicyclo(2.2.1)heptane, 7-azabicyclo(2.2.1)heptene and/or aderivative of this compound.
 7. The administration form as claimed inclaim 1, characterized in that the active compound is ebibatidine and/ora derivative of this compound.
 8. The administration form as claimed inclaim 1, characterized in that the active compound is a benzylidene- andcinnamylidene-annabasiene or a derivative of this compound.
 9. Theadministration form as claimed in claim 1, characterized in that theactive compound is selected from the compound group mecamylamine,hypericin, CP-52655 and buproprion and/or one of their derivatives. 10.The administration form as claimed in claim 1, characterized in that theactive compound is selected from the group of oxazolidinone derivativesand befloxatones.
 11. The administration form as claimed in claim 1,characterized in that the active compound is the cannabinoid receptor(CB 1) antagonist SR 141716.